Investigating key factors underlying neurodegeneration linked to alpha‐synuclein spread

AIMS: It has long been considered that accumulation of pathological alpha‐synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFFs) and 6‐hydroxydopamine (6‐OHDA), because aSyn PFFs induce spreading/accumulation of aSyn, and 6‐OHDA rapidly causes local neuronal loss. METHODS: We injected mouse aSyn PFFs into the medial forebrain bundle (MFB) of Sprague–Dawley rats. We investigated spread of pathological aSyn, phosphorylation of aSyn and tau, oxidative stress, synaptic/neuronal loss and cognitive dysfunction 60, 90 and 120 days after injection. Similarly, we injected 6‐OHDA into the MFB and examined the same parameters 1 and 3 weeks after injection. RESULTS: Following aSyn PFF injection, phosphorylated aSyn was found distant from the injection site in the hippocampus and frontal cortex. However, despite neuron loss being evident close to the site of injection in the substantia nigra at 120 days post injection, there were no other neurodegeneration‐associated features associated with aSyn including synaptic loss. In contrast, 6‐OHDA caused severe neuronal loss in the substantia nigra at 3 weeks post injection that was accompanied by phosphorylation of aSyn and tau, oxidative stress, loss of synaptic proteins, cognitive and motor dysfunction. CONCLUSIONS: Our results demonstrate that spread/replication and slow accumulation of pathological aSyn may not be sufficient to induce neurodegenerative changes. In contrast, oxidative stress responses in addition to aSyn accumulation were associated with other Parkinson's disease (PD)‐associated abnormalities and cognitive dysfunction. Our results may be important when considering why only some PD patients develop dementia.